Fri Feb 18 2022

66 articles - From Saturday Feb 12 2022 to Friday Feb 18 2022

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Guidelines

Guidelines, position statements, white papers, technical reviews, consensus statements, etc…


Meta-analysis

meta-analyses and systematic reviews


Studies

RCT, clinical trials, retrospective studies, etc…

Am J Hematol

A predictive algorithm for identifying children with sickle cell anemia among children admitted to hospital with severe anemia in Africa.

Most outcomes, including mortality and readmission, were better in children with either known or unknown-SCA than non-SCA children. A simple algorithm based on seven admission criteria detected 73% of al children with unknown-SCA with a number needed to test to identify one new SCA case of only two. Our proposed algorithm offers an efficient and cost-effective approach to identifying children with unknown-SCA among al children admitted with severe anemia to African hospitals where screening is not widely available.

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Activity of Decitabine as Maintenance Therapy in Core Binding Factor Acute Myeloid Leukemia.

At a median follow up of 59.3months (13.2-106months) from DAC initiation, sixteen patients (51.6%) had to be initiated on a second line of therapy (40%, 25% and 100% patients respectively in Groups1, 2A and 2B). The median estimated time to new treatment between responders was 112.4months vs 5.8months in non-responders (HR =0.16, 95% CI =0.04-0.54); however, there were no difference in OS between these groups (P = 0.37) CONCLUSION: Decitabine is an effective maintenance therapy for CBF-AML patients with persistent fusion transcript at a low level after FLAG based regimen. Attainment of CMR with DAC maintenance can lead to long term remission in patients who have persistent MRD positive after FLAG based regimen or are unable to receive the full course of consolidation therapy

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Chidamide plus Prednisone, Etoposide, and Thalidomide for Untreated Angioimmunoblastic T-cell Lymphoma in a Chinese Population: A Multicenter Phase II Trial.

The most common grade 3/4 adverse event was neutropenia (n =22, 32.3%). Twelve patients showed treatment-related infections and recovered from antibiotic therapy; the other adverse events were mostly mild and reversible. The oral CPET regimen is an effective, tolerable, and economical choice for untreated AITL in a Chinese population.

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Cost-effectiveness of second-line therapies in adults with chronic immune thrombocytopenia.

The annual cost of TRAs would have to decrease over 80% to begin to become cost-effective in any early TRA strategy. Our data indicate that effectiveness of early TRA and late TRA strategies is similar with the cost significantly greater with early TRA strategies. Contrary to current practice trends and guidelines, early use of splenectomy and rituximab, rather than TRAs, constitutes cost-effective treatment in adults with chronic ITP.

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Immunogenicity of a 5-dose pneumococcal vaccination schedule following allogeneic hematopoietic stem cell transplantation.

IgG concentrations increased significantly over time for al 24 serotypes. Concluding, although immunogenicity of PCV13 serotypes was reasonable, the poor response to PPSV23 serotypes resulted in an insufficient overall response to pneumococcal vaccination for allo-HSCT recipients. Research into vaccination strategies with higher-valent T-cell-dependent pneumococcal vaccines is needed.

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Midostaurin therapy for advanced systemic mastocytosis: Mayo Clinic experience in 33 consecutive cases.

Response to treatment was not predicted by KIT mutation (p = 0.67) or exposure to prior cytoreductive therapy (p = 0.44). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs 16months; p = 0.15). Findings from the current study are broadly consistent with previously published clinical trial observations.

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Risk stratification for relapsed/refractory classical Hodgkin lymphoma integrating pre-transplant Deauville score and residual metabolic tumor volume.

We retrospectively assessed 106 patients with relapsed/refractory cHL who underwent autologous stem cell transplantation. Pre-transplant DS was determined as 1-3 (59%) and 4-5 (41%), with a markedly inferior event-free survival (EFS) in patients with DS 4-5 (hazard ratio [HR], 3.14; P =0.002). High rMTV combination and disease status predict the risk of post-transplant treatment failure and will guide risk-stratified approaches in relapsed/refractory cHL.

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Blood

Cerebral vasculature exhibits dose-dependent sensitivity to thrombocytopenia that is limited to fetal/neonatal life.

By inducing a thrombocytopenic range, we demonstrate that there is a large buffer-zone of mild thrombocytopenia that does not result in ICH, that ICH becomes probabilistic at 40% of normal platelet numbers, and that ICH becomes fully penetrant below 10% of normal platelet number. We also demonstrate that although the neonatal mouse is susceptible to thrombocytopenia-induced ICH, this sensitivity is rapidly lost between post-natal days 7 - 14. These findings provide important insights into the risk of in utero ICH with varying degrees of thrombocytopenia and into defining the developmental high-risk period for thrombocytopenia-driven ICH in a mouse model of FNAIT.

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Defects in mucosal immunity and nasopharyngeal dysbiosis in HSC transplanted SCID patients with IL2RG/JAK3 deficiency.

These patients have a reduction in IgA-coated nasopharyngeal bacteria and exhibit microbial dysbiosis with increased pathobiont carriage. Interestingly, IVIG replacement therapy can partially normalize nasopharyngeal Ig profiles and restore microbial communities in GC/JAK3 patients. Together, our results suggest a potential non-redundant role for type 2 immunity and/or of local IgA antibody production in the maintenance of nasopharyngeal microbial homeostasis and mucosal barrier function.

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Deletion of platelet CLEC-2 decreases GPIba-mediated integrin aIIbb3 activation and decreases thrombosis in TTP.

Importantly, prophylactic oral administration of aspirin, an inhibitor of platelet activation, and therapeutic treatment of the TTP mice with eptifibatide, an integrin aIIbb3 antagonist, reduced pulmonary arterial thrombosis in the TTP mouse model. Our observations demonstrate that GPIba-mediated activation of integrin aIIbb3 has an important role in the formation of thrombosis in TTP. These observations suggest that prevention of platelet activation with aspirin may reduce the risk for thrombosis in patients with TTP.

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Genetics of Inherited thrombocytopenias.

Through collaborative international efforts applying next generation sequencing approaches, the list of genetic syndromes that cause thrombocytopenia has expanded significantly in recent years now with over 40 genes implicated. In this review, we focus on what is known about the genetic etiology of inherited thrombocytopenia syndromes, and how the field has worked to validate new genetic discoveries. We highlight the important role for the clinician in identifying a germline genetic diagnosis, and strategies for identifying novel causes through research-based endeavors.

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Genotoxic aldehydes in the hematopoietic system.

Mammals have evolved a two-tier protection mechanism against aldehydes, consisting of aldehyde detoxification enzymes (tier one), and the Fanconi Anemia (FA) DNA repair pathway (tier two) to process any aldehyde-induced DNA damage. Loss of either tier of protection in humans results in defective hematopoiesis and predisposition to leukemia. This review will focus on the impact of aldehydes on hematopoiesis, how they cause DNA damage, the sources of endogenous aldehydes and potential novel protective pathways.

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Guiding the Global Evolution of Cytogenetic Testing for Hematologic Malignancies.

Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies, and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, technical, and economic implications, we provide points to consider for the global evolution of cytogenetic testing.

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Mapping the Prothrombin Binding Site of Pseutarin C by Site-directed PEGylation.

PEGylation of residues within our proposed binding site greatly reduced the rate of thrombin generation, without affecting the pathway, whilst those outside the proposed interface had no effect. PEGylation of residues within the a1-loop also reduced the rate of thrombin generation. The sequence of the a1-loop was found to play a critical role in prothrombin binding and in the presentation of Arg320 for initial cleavage.

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Molecular Mechanisms of Leukocyte ß2 Integrin Activation.

The integrin activation pathway involves many cytoplasmic signaling molecules such as spleen tyrosine kinase (Syk), other kinases like BTK, phospholipases, PI3kinases, Rap1 GTPases, and the Rap1-GTP-interacting adapter molecule (RIAM). These signaling events ultimately converge on talin-1 and kindlin-3, which bind to the integrin ß cytoplasmic domain and induce integrin conformational changes: extension (E) and high affinity for ligand (H). Here, we review recent structural and functional insights into how talin-1 and kindlin-3 enable integrin activation, with a focus on the distal signaling components that trigger ß2 integrin conformational changes and leukocyte adhesion under flow.

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Primary Plasma Cell Leukemia displaying t(11;14) have specific genomic, transcriptional and clinical feature.

This translated into better overall survival when compared to pPCL without t(11;14) (39.2 months vs 17.9 months, p=0.002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far.

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Safety and Efficacy of Tisagenlecleucel in Primary CNS Lymphoma: A phase I/II clinical trial.

Overall, tisagenlecleucel was well tolerated and resulted in a sustained remission in 3/7 (42.9%) of initial responders. These data suggest that tisagenlecleucel is safe and effective in this highly refractory patient population. Registered as Clinical Trial # NCT04134117.

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Structural basis of Von Willebrand Factor multimerization and tubular storage.

The clinically identified VWF mutations in the propeptide disrupted different steps of the assembling process leading to diminished VWF multimers in von Willebrand diseases (VWD). Overall, these results indicate that the propeptide serves as a pH sensing template for VWF multimerization and tubular storage. This sheds light on delivering normal propeptide as template to rectify the defects in multimerization of VWD mutants.

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Blood Adv

A genetically distinct pediatric subtype of primary CNS large B-cell lymphoma is associated with favorable clinical outcome.

In this multi-institutional study, targeted next-generation DNA sequencing and chromosomal copy number analysis was performed on a cohort of 12 pediatric and YA (age 100 months; 5-year-overall survival: 100%). In conclusion, we have identified a new pediatric type of PCNS-LBCL that is molecularly distinct from PCNS-LBCL occurring in adults, based on an absence of MYD88 mutation, CDKN2A/B homozygous deletion, deletion of HLA gene cluster, and paucity of CD79B and PRDM1 mutations, along with an enrichment for TP53, NFKBIE, and GNA13 mutations. Patients with pediatric type, MYD88-wildtype PCNS-LBCL often have long-term survival compared to their adult counterparts.

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Anti-HK antibody reveals critical roles of a 20-residue HK region for Aß-induced plasma contact system activation.

The 3E8 antibody can also disassemble HK/PK and HK/FXI complexes in normal human plasma in the absence of a contact system activator due to its strong binding affinity for HK, indicating its prophylactic ability. Furthermore, the binding of Aß to both FXII and HK is critical for Aß-mediated contact system activation. These results suggest that a 20-amino acid region of HK's domain 6 plays a critical role in Aß-induced contact system activation, and this region may provide an effective strategy to inhibit or prevent contact system activation in related disorders.

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BTK Inhibitors Impair Humoral and Cellular Responses to Recombinant Zoster Vaccine in CLL.

Antibody titers and T cell responses were not correlated with age, absolute B and T cell counts, or serum immunoglobulin levels (all P > 0.05). RZV induced both humoral and cellular immune responses in treated and untreated CLL patients, albeit with lower response rates in patients on BTKi therapy compared to TN patients. Registered at as #NCT03702231.

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Clinical Activity of Single Dose Systemic Oncolytic VSV Virotherapy in Patients with Relapsed Refractory T-Cell Lymphoma.

Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at as NCT03017820).

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Cost-effectiveness analysis of alternative anticoagulation in suspected heparin-induced thrombocytopenia.

This is the first cost-effectiveness analysis comparing argatroban with fondaparinux and rivaroxaban using primary data. Fondaparinux and rivaroxaban resulted in more averted AE but fondaparinux had greater cost savings. Fondaparinux could be a viable alternative to argatroban.

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Mass spectrometry vs immunofixation for treatment monitoring in multiple myeloma.

After consolidation, IFE was not able to discriminate two cohorts with different median progression free survival (mPFS) but EXENT&FLC-MS did so; further, among IFE negative patients, EXENT&FLC-MS identified two groups with significantly different mPFS (p=0.0008). In conclusion, compared to IFE, EXENT&FLC-MS is more sensitive to detect the M-protein of patients with MM, both at baseline and during treatment, and provides a more accurate prediction of patients´ outcome. This trial is registered at as NCT01916252.

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Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness.

Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit the loss of HSPC and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

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Racial Disparities in Cancer-Associated Thrombosis.

Blacks/African Americans had higher incidence of CAT for al tumor types except myeloma, while Asians/Pacific Islanders had consistently lower incidence of CAT compared to non-Hispanic Whites, after adjusting for potential confounders. The main driver for the racial/ethnic differences was incidence of pulmonary embolism. We speculate the association of race/ethnicity with incidence of CAT may be partially due to underlying thrombotic predisposition that varies by ancestry, but we also must consider the impact of social determinants of health on our results.

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Blood Cancer J

Clinical outcomes with use of radiation therapy and risk of transformation in early-stage follicular lymphoma.

Combined modality treatment did not yield superior survival compared with radiation alone (P>0.05) but was associated with better progression-free survival (HR 0.36, 95% CI 0.14-0.90, p=0.03). The rate of transformation increased steadily over time and was 4.2% at 5 years and 10.8% at 10 years. This modern-era analysis rationalized the role of initial observation in patients with early-stage FL although patients receiving radiation therapy also demonstrate excellent outcome.

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Mass-Fix better predicts for PFS and OS than standard methods among multiple myeloma patients participating on the STAMINA trial (BMT CTN 0702 /07LT).

For OS, the only prognostic pre-I measure was Mass-Fix, and the only 1YR measures that were prognostic on multivariate analysis were 1YR MRD and 1YR Mass-Fix. SIFE and CR were not. Mass-Fix is a powerful means to track response.

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Neutrophil-to-lymphocyte ratio is a novel predictor of venous thrombosis in polycythemia vera.

Moreover, the relative risk in both low- and high-standard risk groups was almost doubled in the presence of NLR=5. These findings were validated in two Italian independent external cohorts (Florence, n=282 and Rome, n=175) of contemporary PV patients. Our data support recent experimental work that venous thrombosis is controlled by innate immune cells and highlight that NLR is an inexpensive and easily accessible prognostic biomarker of venous thrombosis.

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Haematologica

All-oral triplet combination with ixazomib, lenalidomide, and dexamethasone in newly diagnosed transplant-eligible myeloma patients: final results of the phase 2 IFM study 2013-06.

Not available.

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Complement C1s inhibition with sutimlimab results in durable response in cold agglutinin disease: CARDINAL study 1-year interim follow-up results.

Not available.

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Humoral immune-depression following autologous stem cell transplantation is a marker of prolonged response duration in patients with mantle cell lymphoma.

Each arm included 120 patients. Concerning infection incidence and al biological parameters, there was no difference between the 2 arms during the first year post-ASCT. After this period, RM patients were more exposed to fever (p=0.03), infections (p=0.001), hypogammaglobulinemia (p=0.0001) and Ig substitution (p.

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Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 CAR-T in advanced B-cell malignancies.

Patients above these thresholds displayed markedly increased peak IL-6 levels. Our data imply that increased body composition and VAT in particular represent an additional risk factor for severe and early CRS. These findings carry implications for risk-stratification prior to CD19 CAR-T and may be integrated into established risk models.

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NOX2: determinant of acute myeloid leukemia survival.

Not available.

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Outstanding outcomes in infants with KMT2A-germline acute lymphoblastic leukemia treated with chemotherapy alone: results of the Children's Oncology Group AALL0631 trial.

Not available.

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The highly selective Bruton tyrosine kinase inhibitor acalabrutinib leaves macrophage phagocytosis intact.

Not available.

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The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of acute myeloid leukemias.

Moreover, its expression was increased at the surface of patient's chemotherapy resistant AML cells. Using a gene expression-based score we finally demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis in AML patients. The prognosis NOX score we defined is independent of the cytogenetic-based risk classification, FAB subtype, FLT3/NPM1 mutational status and age.

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Vaccine-induced immune thrombotic thrombocytopenia: a possible pathogenetic role of ChAdOx1 nCoV-19 vaccine encoded soluble SARS-CoV-2 spike protein.

Not available.

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Lancet Haematol

Risk factors associated with venous and arterial neonatal thrombosis in the intensive care unit: a multicentre case-control study.

Interpretation Identification of thrombosis-associated risk factors will be useful in developing a risk prediction model to prevent thrombosis and in improving outcomes. The study results add to the knowledge of the differences in risk factors for venous versus arterial thrombosis in neonates and to the understanding of the associations of CAD characteristics with neonatal thrombosis. Funding Bristol-Myers Squibb-Pfizer Alliance.

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Leukemia

Activation and expansion of T-follicular helper cells in chronic lymphocytic leukemia nurselike cell co-cultures.

T-cell receptor (TR) gene repertoire analyses confirmed the clonal expansion of CD4 + T cells, with an enrichment of TR clonotypes commonly expanded also in primary CLL samples. Multicolor confocal microscopy revealed that Tfh, but not Treg co-localize with proliferating CLL cells in CLL lymph node sections. Collectively, these data provide new insight into the cellular and molecular cross-talk between CLL and T-cell subsets, resulting in clonal expansion of T-helper cells and interaction of Tfh cells with proliferating CLL cells which may open new avenues for therapeutic targeting.

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IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells.

Mechanistically, we identified the transcription factors BZW1 and BZW2 as novel cargo of IPO11. We further show that BZW1/2 mediate a transcriptional signature that promotes stemness and survival of LSC. Thus, we demonstrate for the first time how specific cytoplasmic-nuclear regulation supports stem-like transcriptional signature in relapsed AML.

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Targeting the NOTCH1-MYC-CD44 axis in leukemia-initiating cells in T-ALL.

Single-cell proteomics analysis from the PDX model, demonstrated quantitative reduction of LICs (CD34+CD7+CD19-) and downregulation of the NOTCH1-MYC-CD44 axis, along with cell cycle, apoptosis and PI3K/Akt pathways. Moreover, secondary transplantation from PDX and PTEN models of T-ALL, confirmed delayed leukemia development and extended survival of mice engrafted with T-ALL from ARV-825 treated mice, providing functional confirmation of depletion of LICs. Hence, BRD4 degradation is a promising LIC-targeting therapy for T-ALL.

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Thromb Haemost

Active FXI Can Independently Predict Ischemic Stroke in Anticoagulated Atrial Fibrillation Patients: A Cohort Study.

FXIa present in circulating blood is associated with increased risk of ischemic stroke and cardiovascular death in anticoagulated AF patients during long-term follow-up. FXIa inhibition could be useful in cardiovascular prevention in AF beyond the current oral anticoagulation.

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Changes in endocan and dermatan sulfate are associated with biomechanical properties of abdominal aortic wall during aneurysm expansion and rupture.

Our findings reveal a structural association between collagen and PGs and their response to changes in mechanical loads in AAA. Particularly Col1 and endocan reflect the mechano-biological conditions of the aortic wall also in the patient's serum and might serve for AAA risk stratification.

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Human atheromatous plaques expressed sensing adaptor STING, a potential role in vascular inflammation pathogenesis.

Of note, endothelial cells were constantly positive in al cases analyzed. STING expression was strong in the complicated ATC plaques near the cell debris and hemorrhagic foci. Considering these findings, we propose that cGAS-STING signaling plays a role in atherogenesis, opening novel avenues for therapeutic development.

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Katacine is a new ligand of CLEC-2 that acts as a platelet agonist.

We identified katacine, a mixture of polymers of proanthocyanidins, as a novel ligand for CLEC-2 and showed that it induces platelet aggregation and CLEC-2 phosphorylation via Syk- and Src kinases. Platelet aggregation induced by katacine is inhibited by the anti-CLEC-2 monoclonal antibody fragment AYP1 F(ab)'2. Katacine is a novel non-protein ligand of CLEC-2 that could contribute to a better understanding of CLEC-2 activation in human platelets.

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Reviews&Editorials

Plenty of the editorials are available as full text through the publisher website using the provided link

Ann Oncol

Bladder cancer: from a therapeutic wilderness to so many options; a guide to practice in a changing landscape.

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Blood

Adult T-cell leukemia: genomic analysis.

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Detecting HLH in hematologic malignancies.

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PLaCatinG AML1-ETO.

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Reproductive equity: preserve the reserve.

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Telomere biology disorders gain a family member.

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Treating CAR-T relapses: check not checkmate.

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J Hematol Oncol

Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma.

Profound quantitative and qualitative dysfunction of numerous immune effector cell types that confer anti-myeloma immunity further supports myelomagenesis, disease progression and the emergence of drug resistance. Identification of tumor intrinsic and extrinsic resistance mechanisms may direct the design of rationally-designed drug combinations that prevent or overcome drug resistance to improve patient survival. Here, we summarize various mechanisms of immune escape as a means to inform novel strategies that may restore and improve host anti-myeloma immunity.

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Letters&Replies

Letters to the editors and authors’ replies

Am J Hematol

Apixaban has Superior Effectiveness and Safety Compared to Rivaroxaban in Patients with Commercial Healthcare Coverage: A Population-Based Analysis in Response to CVS 2022 Formulary Changes.

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Hemolysis after High-Dose Intravenous Immunoglobulin: an Under-Appreciated Sequelae.

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Prediction of outcomes in cll patients treated with ibrutinib: validation of current prognostic models and development of a simplified three-factor model.

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Others

all remaining publications eg case reports, images of the month, etc…

Blood

Hemophagocytosis in cerebrospinal fluid after CAR T-cell therapy.

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Predicting HLH diagnosis and mortality in cancer.

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Blood Adv

A phase 1 trial of copanlisib plus ibrutinib in relapsed/refractory mantle cell lymphoma.

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Lancet Haematol

Understanding risk factors for neonatal thrombosis.

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Leukemia

Associations of history of vaccination and hospitalization due to infection with risk of monoclonal B-cell lymphocytosis.

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Clonal hematopoiesis of indeterminate potential in the companion dog.

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Human CD34+ very small embryonic-like stem cells can give rise to endothelial colony-forming cells with a multistep differentiation strategy using UM171 and nicotinamide acid.

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Physician and patient perceptions on randomization of treatment intensity for unfit adults with acute myeloid leukemia and other high-grade myeloid neoplasm.

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The potential of cell-free DNA to reveal the molecular profiles of Langerhans cell histiocytosis and Erdheim-Chester disease in adults.

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